Tag: aging

Why is the aging process accompanied by progressive cognitive decline such as impaired memory, decreased focus, and slowed reaction time? Although we don’t fully know what causes it, researchers have found that aging visibly affects the brain, most strikingly as a decrease in total brain volume due to progressive loss of neurons. As we age, it is thought that neurons are irreversibly damaged by cumulative mistakes in building proteins, copying DNA, and other processes.

Sometimes, these mistakes can cause abnormal proteins and other molecules to clump together and form dense deposits inside neurons. In many neurodegenerative diseases such as Alzheimer’s or Lafora’s disease, an excess of deposits is associated with rapid neuron death. Yet although the (albeit much less severe) accumulation of deposits in the brain is a normal part of aging, its role in cognitive decline has been historically ignored. In a new study published in Aging Cell by the Milán and Guinovart labs, researchers investigate why these deposits appear during the normal aging process and what effect they have on neuronal function.

Glycogen is a storage molecule made up of thousands of branching glucose units. Image by Mikael Häggström.

Previous research has shown that the deposits present in aged human brains (which are referred to as either corpora amylacea or polyglucosan bodies; I’m just going to call them PGBs) are primarily made up of glycogen molecules, along with some other proteins. Glycogen is an important energy storage molecule in animal cells (second only to fats) and each glycogen molecule is composed of thousands of glucose units. But what causes the glycogen to aggregate and form deposits in a normal aging brain?

The authors analyzed PGBs in the brains of aged mice to answer this question. They first studied the composition of the mouse PGBs and confirmed that they were similar to the PGBs found in aged human brains, down to the types of proteins bound up among the glycogen molecules. Next, they created a knock-out mouse line that was missing the glycogen synthase gene, which synthesizes glycogen by attaching glucose molecules together. The authors couldn’t find PGBs in the aged brains of these mutant mice, thus demonstrating that the process of synthesizing glycogen contributed to PGB formation. This finding is admittedly unsurprising: if the cells can’t make glycogen, it’s not there to clump together.

Well here’s the interesting part! Not only couldn’t the authors find glycogen deposits, but they also didn’t see accumulation of any of other protein associated with PGBs. One of the proteins they tested was alpha-synuclein, the aggregate-prone protein involved in Parkinson’s disease. In the normal mice, alpha-synclein accumulated along with the PGBs, but there was no accumulation in the mutant mice. Thus, glycogen synthesis seemed to be a prerequisite for the formation of other protein deposits. This finding could have implications for possible treatments to slow aging—if we can interfere with glycogen synthesis, could we stop the accumulation of other damage-causing proteins and reduce the detrimental effects on the brain?

To answer that question, we’d need to first confirm that the PGBs are actually involved in the decline of neuronal function during aging. This leads me to the authors’ next set of experiments, for which they turned to Drosophila melanogaster. Because fruit flies have shorter lifespans, it’s easier to study how PGBs affect them over their entire lives. In addition, fly researchers have developed a vast array of genetic tools for their animal model, which the authors used to knock-out the glycogen synthase gene again, but this time only in the brain and only during adulthood. This allowed the researchers to study how PGB formation affects brain function without altering the development and general health of the fly (a very difficult feat in mice).

As expected, the authors found that the mutant flies had reduced levels of glycogen in the brain. But remarkably, they also found that the mutants lived significantly longer than the normal flies. And this was quality life—the aged mutant flies could climb better and faster than normal flies of the same age. Based on these results, the authors concluded that glycogen synthesis impairs neuronal function and survival with age.

The findings from this paper is a step in the right direction for figuring out why cognitive decline is associated with aging. Before this can be useful for humans, however, there are a lot of questions to answer. How and why does glycogen synthesis cause PGB formation as we age? Will interfering with this process in adulthood extend quality life and cognitive function (and can it be done safely)? Finally, the finding that glycogen synthesis may be required for other protein deposits was completely unexpected. Future work in this field may therefore provide insights into neurodegenerative diseases associated with protein aggregation, such as Alzheimer’s disease (beta-amyloid), Parkinson’s disease (alpha-synuclein), and Lafora’s disease (glycogen!).

For more research on aging, click the “aging” tag in the right column.

As human life expectancy continues to increase at a steady rate in most countries worldwide, the prevalence of aging-related diseases is also increasing. One such example is Alzheimer’s disease (AD), the most common cause of dementia in the aging population. There is currently no cure for AD, and the only treatments that exist temporarily cover up the symptoms without actually slowing the disease itself.

Alzheimer’s disease can be identified by the abnormal accumulation of a protein called amyloid beta (Aβ) in the brain. Aβ is a byproduct of an important cellular process, and is usually cleared away by the cell’s garbage recycling processes. It’s normal for some leftovers to be missed, however, and over time Aβ builds up as we age. But in large enough concentrations—such as in older patients with AD—accumulation leads to the formation of aggregated deposits of Aβ. These deposits damage neurons and cause neurodegeneration (progressive neuron death).

The left side shows healthy neurons. The right side shows damaged neurons and Aβ deposits as seen in Alzheimer’s disease patients. Image modified from alz.org

Eventually, this widespread brain tissue damage leads to imbalances in the levels of neurotransmitters, which are chemicals that neurons use to communicate. This imbalance is thought to cause the symptoms of AD, including problems with memory, thinking, or changes in behavior. Current treatments simply alter the amount of these neurotransmitters without doing anything to slow or prevent Aβ aggregation and neuron death. Therefore, research aimed at developing a drug that can interfere with Aβ accumulation is important for treating this disease.

Recent findings in lithium research holds hope for such a treatment. Although lithium is most widely used as a treatment for bipolar disorder, some preliminary research suggests that it might also be able to slow or prevent the symptoms of Alzheimer’s disease in humans if prescribed early enough. However, the results have been mixed and even sometimes contradictory. This is largely due to the fact that lithium’s actions in the brain are not understood, so figuring out how lithium might be helping AD patients is essential before it could be considered as a treatment. A recent paper published in Frontiers of Aging Neuroscience by the Partridge lab has begun to do just that by studying how lithium can reduce Aβ accumulation in a fruit fly model of Alzheimer’s disease.

The authors created a model for AD by introducing a mutated form of human Aβ protein known to cause AD in some families (called Arctic Aβ42) into adult fruit flies. Flies with the Arctic Aβ42 mutation displayed progressive neuron dysfunction and shortened lifespan, which mimicked the symptoms of AD in human patients. They had previously shown that lithium treatment was able to reduce the amount of Aβ (and thus also its toxic effects on neurons) in these flies. But how did it work? In this study, they treated these mutant flies with lithium again to answer this question.

What they found was surprising. Lithium didn’t just reduce the amount of Aβ protein in the brain, it reduced the amount of all proteins. It worked by suppressing the activity of the “translation machinery”, which refers to the system that actually assembles and produces proteins from the instructions in the genetic code. So lithium actually reduced the production of all proteins through a mechanism that wasn’t specific to Aβ.

What does this mean for the possibility of using lithium to treat Alzheimer’s disease? The fact that lithium’s effects are more general is actually pretty good news not just for AD, but for all research into the aging process. It is currently thought that normal aging is caused by the accumulation of damaged or mutated proteins that haven’t been cleaned up, and research aimed at increasing lifespan has focused on either improving the cell’s recycling processes or reducing protein production. In fact, lithium treatment has been shown to increase life expectancy in animal models, including fruit flies (and possibly even in humans!).

So if lithium can increase lifespan in animals without Alzheimer’s disease, can it reverse the lifespan reduction in the AD model flies? Yes! The authors found that lithium treatment also improved the life expectancy of their mutant flies compared to ones that did not get a lithium treatment. This result provides further hope that lithium could one day be used to actually slow the progression of AD and give patients more years of quality life.

The findings in this paper are not just promising for Alzheimer’s disease, but also for other aging-related diseases caused by abnormal accumulation of protein in the brain, such as Parkinson’s disease and Huntington’s disease. Lithium also has the advantage of already being an approved drug for treating patients with bipolar disease, so some information on side-effects and dosages already exists. Of course, this doesn’t mean doctors should begin prescribing lithium for AD patients right away; the dosage requirements will likely be different and older adults may experience other side-effects. But research in this field has definitely leapt forward, and we may see a cure for aging-related diseases in our (extended?) lifetime.

How can we slow or even halt the steady march of aging? In a previous post, I reviewed a paper that asked “What causes aging?” (the prevailing hypothesis is that aging is caused by accumulating cell damage). Understanding why we age is important for developing ways to interfere with the process. But there are other ways to study aging in the hopes of one day developing the mythical “elixir of life”. A recent fruit fly paper published in Cell Reports by the Walker lab instead asked, “How does caloric restriction increase lifespan?”

Scientists discovered a long time ago that caloric restriction can extend lifespan in a wide range of animal models, including rats and fruit flies. But the diet is severe and leads to side effects including reduced energy levels and sensitivity to cold. Who wants to live longer in such misery? Decreased food intake itself can’t be the cause of increased lifespan (it does seem rather counterintuitive), so what is going on?

The authors found that activating a molecule called AMPK could increase lifespan just like dietary restriction, without all those miserable side effects. Normally, AMPK is activated when a cell needs more energy (such as when the animal isn’t eating enough calories). AMPK then triggers a process called macroautophagy, which means that components and molecules inside of cells are broken down and recycled for energy. This usually happens when the cell needs more energy than it is being provided, and the first things to go are old, unnecessary, and damaged cellular components. By artificially activating AMPK, the authors tricked the cells into breaking down more of this “cellular garbage”, slowing the accumulation of damage that leads to aging.

Perhaps the most exciting finding was that the authors could extend the lifespan of adult flies just by activating AMPK in the intestines. This manipulation slowed aging not just in intestinal cells, but also in brain tissue and even muscles. In fact, older flies even showed improved climbing ability. Although there is much work left to be done, these findings give hope that one day, aging can be slowed in adult humans just by swallowing a pill that activates AMPK in our gut.

Why do we age? It’s more than just a philosophical question; it’s a puzzle that has frustrated scientists for decades. Currently, the most accepted hypothesis is that aging is the result of accumulated damage to our cells during our lifetime. “Accumulated damage” encompasses a variety of things that can go wrong, including DNA mutations, problems in the way molecules such as proteins are built, or abnormal interactions between molecules. Over time, the damage interferes with the body’s ability to maintain itself the way it used to, and the process we call “aging” occurs.

Click on the picture for a bigger version. Multiple external and internal factors can lead to the formation of free radicals and cell damage, which accelerates aging.

It sounds like a great hypothesis, but how can we prove it, and how can we measure accumulated damage? Damage can be caused by a number of factors, and the types of damage that can occur varies wildly between species and even between individuals of the same species. To make matters worse, exposure to certain environmental influences or toxins can accelerate aging. For example, overexposure to UV light from the sun can increase signs of aging in skin cells, and studies have shown that smoking can also accelerate aging. How can scientists study something with so much variability and uncertainty? A recent fruit fly paper published in eLife by the Gladyshev lab describes a new way to study damage accumulation. Instead of measuring the damage itself, they measure the byproducts of cellular metabolism as a proxy.

You see, even if we were able to reduce exposure to environmental toxins, we’d still get older. That’s because unfortunately, even our bodies are working against us. Our cells have metabolic processes, which are the life-sustaining chemical reactions that are needed to keep them alive and reproducing. The small molecules that are produced by these reactions (called metabolites) are usually important for the cells; they could be fuel for energy, signals for growth or reproduction, or even necessary for defenses and interactions with the environment. Unfortunately, these processes also create toxic byproducts such as reactive oxygen species (also known as free radicals). These byproducts cause damage and have often been associated with many age-related diseases such as cancer, heart disease, and Alzheimer’s disease.

To test the idea that accumulating metabolic byproducts can lead to aging, the authors of this study used a new method called “metabolite profiling” to measure the amount of metabolites in flies as they aged. (If you’re interested, the technique they used is called liquid chromatography mass spectrometry). They first found that the diversity of metabolites increases with age. This suggests that mistakes were being made during the metabolic reactions, causing new types of byproducts to appear that can damage cells. Additionally, a subset of metabolites accumulated with age, which may indicate that these byproducts are not being sufficiently cleaned up by maintenance processes in the cells. The authors found that many of these had previously been identified as damaging, directly confirming that accumulating toxic byproducts is correlated with aging.

Finally, the authors also used a calorie-restricted diet to extend the lifespan of a group of flies (although it’s not yet understood why, a severely restrictive diet can increase lifespan in many model animals, including mice and rats. It’s not recommended for humans, however, because there are unpleasant side-effects). Most interestingly, when the authors compared metabolite accumulation in normal flies versus the lifespan-extended flies, they showed that the metabolite accumulation was slower in the longer-lived flies, corresponding with the slower progression of aging.

So how can these findings help us? This paper supports the hypothesis that accumulation of damage leads to aging by showing that metabolites accumulate at a rate that corresponds with relative age in fruit flies. Because most species share the same cellular metabolic processes, these results are relevant to mammals. The next step will be to identify particular types of metabolites and determine how they contribute to aging in flies and mammalian models. The authors of this paper already did some of the legwork. They found that many of the metabolites that differed between the lifespan-extended group and the normal group of flies were associated with processes for using and storing energy from fats and proteins (not surprising considering the flies were on a strict diet). The authors suggest that changing these metabolic processes through diet may have compensated somehow for the accumulation of toxic byproducts. Future research may be able to expand upon these findings, and perhaps even figure out a way to interfere with these processes to slow or alter aging. I just hope I live long enough to see it!